Caloric restriction slows brain aging

Lou Pagnucco wrote:
> Below is a summary of a paper just published in Nature Genetics which
> demonstrates that genes (at least in lab mice) that are upregulated
> during aging in the brain (associated with inflammation and the stress
> response) are repressed by caloric restriction. Presumably, CR should
> retard brain senescence.
>> It is interesting that gene chips were central to this analysis. The
> secrets of the aging process are finally being unraveled.
While I agree with the widespread sentiment that microarray and other
genomic analysis techniques can tell us a great deal about cell biology
in general and aging in particular, I think it may be worth pointing out
the limitations of such work. I participated last weekend in a small
meeting ostensibly focused on reversing human aging; Weindruch also took
part and several other participants were also genomics afficionadios.
I found it necessary to spell out rather forcefully that what we get by
microarray and related experiments is a picture of the **coordinated**
gene-expression changes which occur during aging, and that such changes
are almost entirely descriptive of what cells are doing to *compensate*
for the primary, accumulated losses of function that define the process
of aging and its rate. Those primary processes themselves, by contrast,
are either non-genetic (such as accumulation of protein cross-links or
of lipofuscin), or non-coordinated (such as nuclear or mitochondrial
mutations, which affect different genes (if any) in each cell), or both
(such as cell loss in glands, muscle, heart, some brain areas, etc.).
Even changes that one might guess are moderately uniform within a given
tissue, such as telomere shortening, are now known not to be (such that
one in 10,000 or so dermal fibroblasts shows senescent gene expression
in old age but the rest don't, for example). Moreover, microarray data
give virtually no clue as to the relative importance of these various
primary processes, because the changes they reveal are compensations for
the cumulative effect of all the primary processes mixed together.
This has very profound implications for the utility of microarray data
in anti-aging research. For example, an intervention which restored
the expression levels of many (or all) genes in an elderly individual
to youthful levels in an elderly individual would be predicted to be
*harmful*, because it would be stopping the body from making the best
of a bad job (i.e. reacting, by gene-expression tuning, to the primary
changes listed above). The value of such analyses may in reality be
restricted to the (important, but limited) field of biomarkers of
"biological age". The Nature Genetics study, for example, identifies
"selective" attenuation by CR of gene expression changes which occur
during aging, thereby providing evidence that those genes whose change
in expression was not attenuated are less good markers of biological
age than the ones which did change. Another application which follows
from this is that a candidate CR mimetic (a chemical proposed to trick
the body into thinking it's on CR when it isn't, and thence -- with luck
-- extending one's lifespan) could be evaluated for its likely efficacy
by determining how similar its effects on gene expression are to those
seen in CR. A wider applicability to anti-aging research -- especially
reversal of aging -- is, by contrast, very hard to see. It is therefore
regrettable that many of those involved in such work are allowing this
distinction to become blurred in the public mind -- and, I increasingly
find, in their own.
Aubrey de Grey